Studies of families with neurofibromatosis type 1 (NF1) have demonstrated that the severity of this disease depends on modifier genes in the individuals. We are using a mouse model of the malignancies associated with NF1 in which the Nf1 and p53 gene are mutated on the same chromosome and screening for modifier genes in different strains of mice. Importantly, both Nf1 and p53 are mutated in sporadic forms of glioblastoma and sarcoma, thus the understanding of tumor mechanisms gained from this project may have relevance to sporadic nervous system tumors and well as NF1. Using a combination of mouse genetics and expression profiling in tumors, we have recently identified several regions responsible for resistance to developing malignant peripheral nerve sheath tumors (MPNSTs), and several regions responsible for susceptibility to astrocytoma. The astrocytoma modifier regions affect the location of astrocytoma and the differential susceptibility of males and females. We have identified a candidate modifier gene on mouse chromosome 11 affecting MPNST susceptibility, and are working to identify additional candidate modifier genes on other chromosomes. These candidate modifiers will then be tested for their role in tumorigenesis in our mouse model and then in human cancers. During fiscal year 2011, we have completed genetic analysis showing that the imprinted gene Grb10 on mouse chromosome 11 acts in a haploinsufficient, tumor suppressive modifier when mutated in our model system. We have extended our studies to the mechanism of action of Grb10, focusing on which signal transduction pathways it affects and which cell biological processes in alters. We are continuing to refine the mapped location of the Nstr1 modifier locus on Chr 19 and are testing candidate genes using overexpression and knockdown approaches. We are taking advantage of human MPNST data to test candidates in collaboration with investigators at Washington University. To identify modifiers of astrocytoma, we have completed the analysis of 600 backcross mice in collaboration with a group at University of Wisconsin. Our analysis shows that the genetic of astrocytoma susceptibility is complex, context-dependent, and different for males and females. We have identified an astrocytoma resistance locus in males (Arlm1) and have used cross-species comparison with REMBRANDT and TCGA datasets to narrow down candidate modifier genes (manuscript under revision). We have begun collaborating with members of the GLIOGENE consortium at MD Anderson to examine whether the same genes affect male risk for glioma in humans. In addition to the male-specific Arlm1 locus, we have also identified a modifier for spinal cord resistance to astrocytoma (Scram1). This is a tumor location-specific modifier, affecting resistance to astrocytoma primarily in the spinal cord but not brain (manuscript submitted). Because spinal cord astrocytomas are so rare, very little is known about their biology from patient samples. The identification of this locus may provide a key to unlocking the biology of spinal cord astrocytomas. To begin to unravel this, we have established an early stage collaboration with investigators at Johns Hopkins University who are collecting spinal cord astrocytomas and performing genome-wide molecular analysis of samples. We will compare mouse and human data as the human data becomes available.